TRANSFORMING GROWTH FACTOR-β PREVENTS THE ACUTE PLATELET ACTIVATING FACTOR-INDUCED INCREASE IN INTESTINAL MUCOSAL PERMEABILITY IN JUVENILE RATS.• 721

Platelet activating factor (PAF) has been implicated as an important mediator of bowel injury in necrotizing enterocolitis. In adult animal models of PAF-induced bowel injury, one of the earliest effects of PAF is an acute increase in intestinal mucosal permeability that may then permit intestinal bacteria and their toxins to gain access to intestinal tissues. However, the pathophysiologic effects of PAF have not been studied in the immature animal. We determined the acute effects of PAF on intestinal mucosal permeability in Sprague-Dawley rat pups aged 15-17 days. We also explored the effects of the anti-inflammatory cytokine, transforming growth factor-β (TGF-β), in this model. Mucosal permeability in a 5-7 cm loop of distal ileum was determined by measuring blood-to-lumen clearance of⁵¹Cr-EDTA, a low-molecular-weight compound that readily equilibrates between tissue and plasma but does not cross intact intestinal epithelium. After surgical preparation and stabilization, baseline ⁵¹Cr-EDTA clearance was measured. Animals were then injected with 1.5 μg/kg PAF and either 20μg/kg TGF-β or placebo. ⁵¹Cr-EDTA clearance was serially measured for 90 minutes following PAF injection. At the end of the experiment, the perfused intestinal segment was snap-frozen in liquid nitrogen for later determination of myeloperoxidase activity, an index of tissue neutrophil content. We found that mucosal permeability significantly increased by 15 minutes following PAF injection (⁵¹Cr-EDTA clearance 191±42% of baseline) but then returned to baseline. This acute increase in permeability was prevented by TGF-β administration (clearance 95±9% of baseline, p=.02). PAF caused an acute decrease in blood pressure that was not prevented by TGF-β, although TGF-β-treated animals tended to have higher blood pressures at later time points. Intestinal myeloperoxidase activity was similar between the two groups. We conclude that TGF-β effectively prevents the acute PAF-induced increase in mucosal permeability in the immature intestine. Although the mechanism of TGF-β action in this model remains to be elucidated, our findings suggest that TGF-β may play a significant role in preventing the pathologic effects of PAF in the immature intestine.